The present invention relates to a Transdermal Drug Delivery System (TDDS) (a transdermal patch), to a method for manufacturing such system, and to the use of such system for hormone replacement therapy.
Estrogens are hormones which are necessary for the sexual development of females at puberty and for the maintenance of the oestrous cycle and secondary sexual characteristics. Estrogens and progesterone induce changes in the reproductive tract and elsewhere in the body of females during the menstrual cycle. Blood estrogen concentrations must be above a certain level for the maintenance of both proliferate and (together with progesterone) secretory phases of the uterine endothelium.
The menopause occurs when menstruation ceases and indicates the end of a woman""s reproductive life; during this phase of a woman""s life there is a progressive loss of ovarian functions and there is a decrease in the production of Estradiol and other hormones.
About 40% of women develop menopausal symptoms serious enough to require medical treatment; the symptoms include mainly vasomotor instability (hot flushes and sweating) and mood and sleep disturbances; during menopause, there is a gradual decrease of bone mass due to a loss of the modulating effect of Estradiol on bone resorption and this process normally leads to osteoporosis. The loss of estrogenic activity changes also the lipid metabolism with a decrease of the ratio of high density lipoprotein (HDL) to low-density lipoprotein (LDL), and this change increases the risk of cardiovascular diseases.
All these negative effects that can occur in a woman in menopause can be eliminated or at least reduced by an appropriate replacement therapy with estrogen agents, i.e. by the xe2x80x9cHormonal Replacement Therapyxe2x80x9d (HRT).
Oral administration of estrogens as HRT has been extensively used for about 30 years and it was confirmed that, besides the climacteric symptoms, HRT was effective in reducing the death by cardiovascular diseases.
However, although oral estrogens are effective as HRT, related adverse effects are a problem; a high amount (60-90%) of the oral estrogens are converted within the gut wall and liver to inactive metabolites having hepatic adverse effects, therefore relatively high doses of oral estrogens are required to compensate sate first-pass metabolism.
Several non-oral formulations of estrogens, which avoid hepatic first-pass effects, have been developed and used as HRT; they include subcutaneous implants, intramuscular injections, vaginal creams and percutaneous gels. However, with such preparations, control of dosage is difficult and patients compliance is poor.
More recently, transdermal preparations delivering Estradiol at a constant rate have become available. In women with an intact uterus estrogens produce hypertrophy of the endometrium which could provoke cancer. In order to minimize the risk of endometrial hyperplasia and carcinoma of the estrogen therapy in women with an intact uterus the treatment must be opposed intermittently by a progestogen to be associated to the estrogen. The opposition therapy normally is carried out by oral administration of a progestogen like medroxyprogesterone acetate, norethindrone, norethindrone acetate, progesterone, etc. for 10-14 days per month.
A patch delivering both Estradiol and a progestogen is an useful alternative to a method which combines the transdermal administration of Estradiol with the daily oral administration of progestogen. Compliance is likely to be further improved and side effects minimized thanks to a lower progestogen dosage requirement compared with oral therapy.
Several problems, however, are encountered when including a progestogen in a transdermal patch. Among these one important obstacle is the low, therapeutically uneffective drug release obtained with a transdermal patch of relatively small size; this is due to the poor skin permeation properties of steroid hormones. Another obstacle is the low stability of some progestogens that leads to degradation products.
In the light of the aforementioned art, there is a need for an optimal transdermal drug delivery system releasing Estradiol and a progestogen through an intact skin resulting in a constant systemic absorption rate.
Numerous patents refer to the delivery of steroid hormones to the systemic circulation via a transdermal route, and some of them refer to transdermal systems containing Estradiol and Norethindrone Acetate.
Some inventions refer to the discovery of special matrix formulations containing substances able to reduce the re-crystallization of Estradiol and Norethindrone. Indeed, it is well known for scientists skilled in TDDS that, in order to obtain an adequate release of steroid hormones from transdermal patches, it is necessary to reach in the matrix high concentrations of the hormones (high drug load) or to significantly increase the release area of the patch. The first solution, however, leads quite often to re-crystallization of the hormones during the shelf-life of the product with consequent reduction of the drug release; the second solution often is not acceptable since it reduces patient compliance because of the size of the patch and even could have a negative effect on the adhesivity of the patch during the intended period of use of the product.
A third possibility to reach an adequate flux from matrix transdermal patches is the inclusion of absorption enhancers (penetration enhancers) in the matrix formulation to generate a high flux of the active compounds when the system is applied to the skin. Typical known enhancers are ethanol, glycerolmonolaurate, DMF, polyethylenglycole monolaurate, etc. Absorption enhancers, however, provoke skin reactions and systemic side effects and this aspect reduces the ratio efficacy/tolerability of the resulting transdermal systems. They increase the permeability of the stratum corneum of the skin through a modification of the cellular layer, provoking lesions of the skin; they can moreover be absorbed by the skin provoking systemic side effects.
Another problem known by skilled researchers in TDDS formulations is the low stability of Norethindrone Acetate in acrylic based formulations that leads to degradation products.
WO 96/03119 (PCT/EP 95/02938) relates to a device for the administration ministration of Estradiol alone or in combination with progestogen(s), encompassing a specific penetration enhancer that achieves elevated transdermal fluxes and optionally an anti-oxidant that achieves good product stability; however, as mentioned above, penetration enhancers can provoke skin reactions.
WO 94/23707 (PCT EP 94/01231) describes an active substance containing laminated plasters with a carrier and a matrix made of one or two polymers, as well as Vitamin E (tocoferol); tocoferol, however, is not free of potential skin reactions in an occlusive patch that has to remain attached to patient skin for 3-4 days.
U.S. Pat. No. 4,379,454 refers to a transdermal liquid reservoir patch which contains Estradiol in an alcoholic gel solution; the alcohol contained in the reservoir, however, acts also as an absorption enhancer and can provoke skin reactions.
WO 9740792 A discloses a matrix type patch for transdermally administering ministering a steroid hormone which comprises a skin permeation enhancing amount of a diethanolamide of a 12-18 C fatty acid.
WO 95/09618 (PCT/EP 94/03269) describes the use of octyldodecanol as crystallization inhibitor in matrix patches containing Estradiol and Norethindrone Acetate.
DE 44 29 664 refers to a transdermal therapeutic system containing Estradiol and a water absorbing additiv, which is part of the matrix. The system according to this document does not contain a progestogen agent and is said to be applicable to Estradiol only.
A system for the application of norethisterone acetate is disclosed in DE 195 48 332. It is, however, stated in this document that the addition of an Aerosil to a matrix does not result in a reduced formation of degradation products of norethisterone acetate.
The object of the invention is the development of a TDDS for HRT releasing Estradiol and at least one progestogen with improved skin permeation of the hormones compared to prior art.